There is strong evidence that genetic susceptibility is necessary for the development of diabetic nephropathy. Our research so far showed that genes involved in susceptibility to diabetic nephropathy may be different in type 1 and type 2 diabetes. The proposed research aims to identify a putative gene on chromosome 7q that seems to contribute specifically to susceptibility to diabetic nephropathy in type 2 diabetes. In addition, we will search for other chromosomal regions that harbor a major susceptibility locus for diabetic nephropathy in type 2 diabetes. The study design is based on sib-pairs with type 2 diabetes that are discordant for diabetic nephropathy (DSP). These families will be used for linkage analysis as well as for association studies using the Sibling Transmission Disequilibrium Test (s-TDT) approach. The specific aims of the proposed research are: 1) To establish two panels of sibling pairs that are concordant for type 2 diabetes and discordant for diabetic nephropathy (DSP): Already recruited is a Screening Panel of 89 extended families to be examined further to increase the specificity of nephropathy diagnoses; To be recruited is an Extension Panel of at least 200 nuclear families having a DSP, and groups of cases and controls for studies of the genetics of diabetic nephropathy. 2) To examine the promising chromosomal region on chromosome 7q for a locus contributing to susceptibility to diabetic nephropathy in type 2 diabetes; 3) To search for other chromosomal regions segregating with diabetic nephropathy in the Panels of DSPs using a chromosome specific panel of genetic markers; 4) To narrow chromosomal regions with evidence of linkage by genotyping panels of DSPs for additional markers in those regions and to initiate positional cloning of susceptibility genes for diabetic nephropathy in the most promising regions. The research has great significance given the current "epidemic" of end-stage renal failure due to type 2 diabetes in the U.S. population. Further, based upon our existing data, the probability of identifying genes for susceptibility to diabetic nephropathy in type 2 diabetes is very high. The innovation of this proposal is the study of genetic susceptibility for diabetic nephropathy in type 2 diabetes using a DSPs study design. This study design seems to be more efficient in detecting linkage for nephropathy than the traditional ASP (affected sib-pair) design.